The importance of opsonic protein in the regulation of the reticuloendothelial (RE) or macrophage system following tumor growth was investigated. Both phagocytic as well as plasma opsonic activity was evaluated in tumor bearing animals following challenge with Walker 256 carcinoma tumor cells. It was observed that phasic alterations of the macrophage system during both periods of R.E. stimulation as well as R.E. failure was due to an associated alteration in the plasma opsonin level. Opsonic protein has been isolated from rat serum and partially characterized. It is an alpha-2 acid glycoprotein with a strong dependence on heparin for expression of its biological activity. Its molecular weight at 4 degrees C, is 800,000 daltons and at 37 degrees is 400,000 daltons. The opsonic protein stimulates macrophage phagocytosis in vitro and can enhance phagocytosis in vivo during a state of R.E. depression. Antiserum made against the opsonic protein will depress phagocytosis in vitro and induce a state of in vivo R.E. depression following intravenous administration. Evaluation of the ability for opsonic protein to inhibit tumor growth demonstrated that the administration of this protein at the site of tumor transplantation will significantly impair the growth of the tumor in experimental rats. Administration of viable tumor cells intravenously during a period of postoperative R.E. depression leads to a decreased clearance of the tumor cells by the R.E.S. with an increased localization of these tumor cells in the lung. Opsonin administration in the form of opsonin therapy during the period of post-operative hypo-opsonemia and R.E. depression will elevate the plasma opsonin level. These studies suggest that opsonic protein acting through the macrophage system may play a major role in host defense against malignant disease. The monitoring of plasma opsonin levels in humans may have both diagnostic as well as prognostic value.